Despite the almost unparalleled impact of small pox on human history, our knowledge and understanding of the molecular and cellular biology and the pathophysiology of Variola infection are severely limited, as a paradoxical result of the eradication of naturally-occurring smallpox in 1977 and the ensuing restrictions on work with the Variola virus. Today, as we face the suddenly renewed threat of smallpox outbreaks, there is an urgent need to develop, as quickly as possible, a systematic understanding of the molecular, cellular and organismal biology of Variola infection. A detailed understanding of the molecular and cellular events in smallpox infection will provide a crucial foundation for rational development of strategies for treating the disease and managing its spread. [unreadable] [unreadable] The recent emergence of significant Monkeypox outbreaks in the human population in Africa highlights the broader importance of orthopoxviruses as potential threats to public health. Parallel studies of Monkeypox and Vaccinia will therefore be important elements of a comprehensive strategy to map the common molecular features of poxvirus infection and to define the unique mechanisms that Variola and Monkeypox employ to thwart or subvert the host's defense mechanisms. [unreadable] [unreadable] The long-term objectives of this proposal are to elucidate the replication and virulence mechanisms of Variola virus and related poxviruses in their primate hosts, and provide insights and tools that can lead to diagnostic, therapeutic, and preventative strategies for smallpox and other poxvirus diseases. The short-term objectives are to construct a systematic, detailed map of the viral and host gene expression programs in Variola and Monkeypox infections, to relate specific features of the gene expression programs to cellular molecular and physiological features of the host-virus interactions, and to characterize the molecular mechanism of a viral strategy for thwarting a critical host defense mechanism. [unreadable] [unreadable] The specific aims of this proposal are 1) to characterize Variola virus and Monkeypox virus infection of primate cells, with emphasis on cytokine and receptor expression, gIobal host and viral gene expression profiles, and host cell response as a function of cell type; 2) to characterize the responses of cynomolgus macaques to infection by Variola and Monkeypox viruses, with emphasis on host defense molecules, pathology, cell tropism; and correlations with gene expression patterns; and 3) to define the molecular mechanisms used by Variola and Monkeypox viruses to alter host interferon responses in vitro. [unreadable] [unreadable] [unreadable]